Lower urinary tract consists of bladder and urethra. The lower urinary tract has the function of collecting urine in the bladder and the function of expelling the collected urine. At the 2002 International Continence Society, it was suggested to define abnormality of the lower urinary tract as lower urinary tract dysfunction and to define various symptoms caused by the result of the lower urinary tract dysfunctions as lower urinary tract symptoms.
Lower urinary tract symptoms are roughly divided into 3 categories: storage symptoms, voiding symptoms, and post micturition symptoms (Abrams P et al.: The Standardisation of Terminology of Lower Urinary Tract Function. Neurourology and Urodynamics 21:167-178, 2002).
Storage symptoms are those wherein urine does not accumulate in the bladder, or what is known as frequent urination (pollakiuria) or urinary incontinence.
The following examples of the storage symptoms are included below.
1) Increased daytime frequency: the voicing in the daytime occurs too often.
2) Nocturia: the individual must wake up at night one or more times in order to void.
3) Urgency: sudden compelling desire to pass urine, which is difficult to defer.
4) Urinary incontinence: involuntary leaking of urine.
5) Urge urinary incontinence: involuntary leakage of urine accompanied by or immediately preceded by urgency.
6) Stress urinary incontinence: involuntary leakage of urine that occurs on abdominal pressure, or on coughing and sneezing.
7) Mixed urinary incontinence: a combination of urge urinary incontinence and stress urinary incontinence are experienced.
Voiding symptoms are experienced during the voiding phase, and are pointed out to be symptoms in which voiding is difficult. Specifically, the following symptoms are included.
1) Slow stream: reduced urine flow.
2) Splitting: urine stream splits.
3) Intermittent stream: urine stream stops and starts more than once during micturition.
4) Hesitancy: a delay in the onset of voiding after the individual is ready to pass urine.
5) Straining: abdominal pressure is needed to initiate, maintain, or improve the urinary stream.
6) Terminal dribble: the termination of micturition is prolonged and the urine flow slows to a dribble.
Post micturition symptoms are symptoms seen immediately after micturition. Specific examples of the following are included.
1) Feeling of incomplete emptying: the feeling that the bladder has not been completely emptied after passing urine.
2) Post micturition dribble: the involuntary loss of urine immediately after voiding; Males will experience this symptom immediately after leaving the toilet whereas females will experience this symptom after rising from the toilet.
Moreover, genitourinary pain and lower urinary tract pain are mentioned under the lower urinary tract symptoms category, as symptoms alongside the above-mentioned storage symptoms, voiding symptoms, and post micturition symptoms in the above article (Abrams P et al.: The Standardisation of Terminology of Lower Urinary Tract Function. Neurourology and Urodynamics 21:167-178, 2002).
From the above article, examples of lower urinary tract pain include the following symptoms:
1) Bladder pain: the pain felt in the suprapubic region and retropubic region. Bladder pain usually increases with bladder filling, and may persist after micturition.
2) Urethral pain: pain felt in the urethral area.
A lower urinary tract disease generally means all diseases which cause a lower urinary tract symptom and includes various functional disorders and diseases in the bladder, the prostate gland and the urethra. Specifically, the diseases in females occur in areas such as the bladder and urethra, while the diseases in males occur in the areas such as the bladder, urethra and also in the prostate gland.
Diseases of the bladder include, for example, uncomplicated cystitis, hemorrhagic cystitis, interstitial cystitis, bladder neck sclerosis, neuropathic bladder, contracted bladder, overactive bladder, underactive bladder and other bladder-related diseases.
Diseases of the prostate gland include, for example, acute or chronic bacterial prostatitis, chronic nonbacterial prostatitis, benign prostate hyperplasia, other prostate-related diseases and the like.
Diseases in the urethra include, for example, urethritis and urethrostenosis and other urethra-related diseases.
Cystitis refers to infectious or non-infectious inflammation which mainly arises in the bladder mucous membrane and submucosal tissue. Clinically, storage symptoms, voiding symptoms, post micturition symptoms and lower urinary tract pain are observed. Generally cystitis is divided into acute and chronic form on the basis of clinical progress. Depending on the presence or absence of obstructive disease in the lower urinary tract, cystitis is classified into uncomplicated cystitis and complex cystitis. Generally uncomplicated cystitis proceeds acutely and responds well to antimicrobial drugs. Complex cystitis proceeds chronically and often does not respond well to antimicrobial drugs and is thus sometimes referred to as intractable cystitis. Intractable cystitis includes hemorrhagic cystitis, interstitial cystitis, bacterial intractable cystitis and eosinophilic cystitis (Schaeffer A J et al.: Chapter 8 Infections of the Urinary Tract, Bladder Infectious Uncomplicated Cystitis, in Campbell-Walsh Urology, 9th ed.: Elsevier, Philadelphia 254-259, 2007).
Hemorrhagic cystitis, which has symptoms of cystitis, is characterized primarily by the presence of heavy hematuria. It can be caused in a number of different ways.
Main causes are
1) Viruses such as adenovirus and influenza;
2) Microorganisms including bacteria such as Escherichia cob, Proteus and Pseudomonas aeruginosa; 
3) Chemical stimulation by anticancer drugs such as cyclophosphamide;
4) Physical stimulation by radiation exposure and the like.
Interstitial cystitis is a disease of the bladder in which the main complaints include urgency, pollakiuria, lower abdominal pain and other complaints include incomplete bladder emptying, malaise and anxiety. The causes are thought to be derived from lymphatic system disorders, chronic infectious diseases, nervous system disorders, mental disorders, autoimmune disease, destruction of defense mechanism in the urinary bladder, mast cell and so on. However the true etiology is not clear (Hanno P M et al.: Chapter 10 Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders, in Campbell-Walsh Urology, 9th ed. Elsevier, Philadelphia 330-349, 2007).
A typical form of bacterial intractable cystitis is bladder tuberculosis. Bladder tuberculosis exhibits clear symptoms of cystitis and pyuria; and conventional antibacterial drugs are not effective for treatment. Acid-fast stain and tubercle bacillus cultures are used to diagnose urinary tract tuberculosis. Cystoscopic examination reveals distinct yellow papule nodules and this was diagnosed as bladder tuberculosis. Treatment by administration of a tuberculostatic agent is effective.
Eosinophilic cystitis exhibits symptoms similar to those of acute bacterial cystitis and pyuria. However, the urine culture is negative and antimicrobial drugs are not effective. This pathological condition is caused by an allergic reaction against drugs with antiallergic properties. Typical examples of such drugs include Tranilast. But other antiallergic drugs may also induce cystitis. Pyuria contains mainly eosinophils. But when eosinophils are absent, polynuclear leucocytes and lymphocytes can be present. Eosinophilic cystitis could be alleviated by withdrawing the drugs which induced the symptoms. However, when the symptoms are difficult to alleviate, administration of steroids is performed.
Acute prostatitis is caused mostly by bacterial inflammation. Typical examples of inflammation-inducing bacteria include gram-negative rod-shaped bacteria, particularly Escherichia coli. When a patient with a history of urinary tract infections is affected with acute prostatitis, inflammation-inducing bacteria of the disease is gram-negative rod-shaped bacteria such as Pseudomonas aeruginosa and Serratia in the same manner as so-called complicated urinary tract infections. Moreover, although the occurrence is not high, Enterococcus and Staphylococcus aureus can be the inflammation-inducing bacteria present. Generally symptoms include lower urinary tract pain and high fever accompanied by shivering and chills. This is a pathological condition that can be easily diagnosed by the swelling of the prostate, tenderness and urinary findings (Nickel J C et al.: Chapter 23 Prostatitis, Orchitis, and Epididymitis: Prostatitis, in Diseases of the Kidney and Urinary Tract, 8th ed. Lippincott Williams & Wilkins, Philadelphia, 634-649, 2007).
Chronic prostatitis is divided into chronic bacterial prostatitis and chronic nonbacterial prostatitis. In the clinical setting, voiding symptoms, post micturition symptoms and lower urinary tract pain are present. In severe cases, the urine storage ability is affected and storage symptoms are seen. It is thought that the route of infection of chronic bacterial prostatitis follows the same route as acute prostatitis; firstly where acute prostatitis becomes chronic and secondary where the chronic bacterial prostatitis proceeds from onset. Symptoms are the irritative symptoms that occur during micturition such as pollakiuria, feeling of incomplete emptying and lower urinary tract pain. The degree of these symptoms is lower than that of the acute stage. Cases of chronic nonbacterial prostatitis occur very frequently, yet the causes are not clearly understood. Chronic nonbacterial prostatitis cannot be distinguishable from bacterial prostatitis based on its symptoms and prostate palpation. When the preceding urinary tract infection is not observed and urinalysis and post-massage prostate fluid cannot verify the presence of bacteria, the presence of leukocytes is used to diagnose chronic nonbacterial prostatitis (Nickel J C et al.: Chapter 23 Prostatitis, Orchitis, and Epididymitis: Prostatis, in Diseases of the Kidney and Urinary Tract, 8th ed. Lippincott Williams & Wilkins, Philadelphia, 634-649, 2007).
Benign prostatic hyperplasia refers to a pathological condition in which hypofunction of the prostate due to aging induces formation of fibromuscular or glandular nodules on the glands surrounding the urethra. These nodules gradually enlarge resulting in an overall enlargement of the prostate. Benign prostatic hyperplasia itself is a benign disease. But when the disease progresses causing the prostate to expand, the disease causes the obstruction of the urinary tract, resulting in lower urinary tract dysfunctions and renal dysfunctions. Clinically, symptoms of benign prostatic hyperplasia mainly include voiding symptoms, post micturition symptoms and lower urinary tract pain. In severe cases, the urine collecting ability of the bladder is affected and storage symptoms are seen.
In recent years, due to an aging society, lower urinary tract symptoms and lower urinary tract pain pose big problems in nursing and clinical care. Lower urinary tract symptoms and lower urinary tract pain are considered to be caused by complicated causes such as cerebrovascular diseases and neurodegenerative diseases as well as lower urinary tract diseases.
So far some therapeutic agents for lower urinary tract diseases have already been introduced. For example there are alpha-1 blockers that treat hypofunction of micturition and benign prostatic hyperplasia such as tamsulosin and naftopidil; anticholinergics that treat pollakiuria and urinary incontinence such as oxybutynin hydrochloride and propiverine hydrochloride; and smooth muscle relaxants that treat pollakiuria and urgency such as flavoxate hydrochloride and the like (Zermann D H et al.: Chapter 22, Disorders of Micturition: Treatment of Lower Urinary Tract Dysfunction, in Diseases of the Kidney and Urinary Tract, 8th ed., Lippincott Williams & Wilkins, Philadelphia, 621-625, 2007).
In recent years, it has been reported a compound which has an affinity for a 5-HT1A receptor and is effective in the treatment/prevention of lower urinary tract disease (U.S. Pat. No. 5,990,114). It has also been reported that a tetrahydroisoquinoline-derivative, which is an agent that depresses a capsaicin-sensitive sensory nerve, is effective on interstitial cystitis, hypersensitivity in the lower urinary tract and nonbacterial prostatitis (U.S. Pat. No. 7,335,668).
However, from the viewpoint of effectiveness and safety, the development of a new therapeutic agent for a lower urinary tract disease and a new agent for improving a lower urinary tract symptom still have been needed.